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Schlagwörter:
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Zusammenfassung:
Dysfunction of protein quality control contributes
to the cellular pathology of polyglutamine (polyQ)
expansion diseases and other neurodegenerative
disorders associated with aggregate deposition.
Here we analyzed how polyQ aggregation interferes
with the clearance of misfolded proteins by the
ubiquitin-proteasome system (UPS). We show in a
yeast model that polyQ-expanded proteins inhibit
the UPS-mediated degradation of misfolded cytosolic
carboxypeptidase Y* fused to green fluorescent
protein (GFP) (CG*) without blocking ubiquitylation or
proteasome function. Quantitative proteomic analysis
reveals that the polyQ aggregates sequester
the low-abundant and essential Hsp40 chaperone
Sis1p. Overexpression of Sis1p restores CG* degradation.
Surprisingly, we find that Sis1p, and its
homolog DnaJB1 in mammalian cells, mediates the
delivery of misfolded proteins into the nucleus for
proteasomal degradation. Sis1p shuttles between
cytosol and nucleus, and its cellular level limits the
capacity of this quality control pathway. Upon
depletion of Sis1p by polyQ aggregation, misfolded
proteins are barred from entering the nucleus and
form cytoplasmic inclusions.
